CD4 enhances T cell sensitivity to antigen by coordinating Lck accumulation at the immunological synapse.
How T cells respond with extraordinary sensitivity to minute amounts of agonist peptide and major histocompatibility complex (pMHC) molecules on the surface of antigen-presenting cells bearing large numbers of endogenous pMHC molecules is not understood. Here we present evidence that CD4 affects the responsiveness of T helper cells by controlling spatial localization of the tyrosine kinase Lck in the synapse. This finding, as well as further in silico and in vitro experiments, led us to develop a molecular model in which endogenous and agonist pMHC molecules act cooperatively to amplify T cell receptor signaling. At the same time, activation due to endogenous pMHC molecules alone is inhibited. A key feature is that the binding of agonist pMHC molecules to the T cell receptor results in CD4-mediated spatial localization of Lck, which in turn enables endogenous pMHC molecules to trigger many T cell receptors. We also discuss broader implications for T cell biology, including thymic selection, diversity of the repertoire of self pMHC molecules and serial triggering.
Duke Scholars
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Related Subject Headings
- T-Lymphocytes
- Signal Transduction
- Receptors, Antigen, T-Cell
- Models, Immunological
- Mice
- Major Histocompatibility Complex
- Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
- Lymphocyte Activation
- Immunology
- Image Processing, Computer-Assisted
Citation
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- T-Lymphocytes
- Signal Transduction
- Receptors, Antigen, T-Cell
- Models, Immunological
- Mice
- Major Histocompatibility Complex
- Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
- Lymphocyte Activation
- Immunology
- Image Processing, Computer-Assisted